Abstract
Wnt/Wingless (Wg) signaling is critical in development and disease, including cancer. Canonical Wnt signaling is mediated by β-catenin/Armadillo (Arm in Drosophila) transducing signals to the nucleus, with IFT-A/Kinesin 2 complexes promoting nuclear translocation of β-catenin/Arm. Here, we demonstrate that a conserved small N-terminal Arm[34][-][87]/β-catenin peptide binds to IFT140, acting as a dominant interference tool to attenuate Wg/Wnt signaling in vivo. Arm[34][-][87] expression antagonizes endogenous Wnt/Wg signaling, resulting in the reduction of its target expression. Arm[34][-][87] inhibits Wg/Wnt signaling by interfering with nuclear translocation of endogenous Arm/β-catenin, and this can be modulated by levels of wild-type β-catenin or IFT140, with the Arm[34][-][87] effect being enhanced or suppressed. Importantly, this mechanism is conserved in mammals with the equivalent β-catenin[24][-][79] peptide blocking nuclear translocation and pathway activation, including in cancer cells. Our work indicates that Wnt signaling can be regulated by a defined N-terminal β-catenin peptide and thus might serve as an entry point for therapeutic applications to attenuate Wnt/β-catenin signaling.
